gp100 (86-95)

Background: Non-small cell lung cancer (NSCLC) is the predominant type of lung cancer, and most clinically curable patients are diagnosed with locally advanced disease. Although the efficacy of standard platinum-based chemotherapy doublets is relatively limited. The effect of immune checkpoint inhibitors (ICIs) remains controversial, and its role in the first-line treatment of advanced NSCLC is obscure. Thus, we carried out a systematic review and meta-analysis to compare the efficacy and safety of ICIs for advanced NSCLC. Methods: The PubMed, Cochrane Central Register Trial, and American Society of Clinical Oncology databases were searched from inception to 30 April 2018. We searched for randomized controlled trials comparing single-agent programmed cell death protein 1/programmed death-ligand 1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) or cytotoxic T-lymphocyte-associated antigen 4 inhibitor (ipilimumab) with chemotherapy in NSCLC patients. Progression-free survival, overall survival, objective response rate, and adverse events were pooled for meta-analysis by Review Manager (RevMan version 5.3) software. Results: After exclusion of ineligible studies, 12 eligible randomized controlled trials were included. Data showed that ICIs significantly improved progression-free survival (HR 0.66, 95% CI 0.57-0.77, P < 0.00001), overall survival (HR 0.77, 95% CI 0.64-0.91, P = 0.003), and but not objective response rate (RR 1.97, 95% CI 1.25-3.13, P = 0.004) in all unselected NSCLC populations. However, they failed to increase the OS of programmed death-ligand 1 = 1-49% subgroup (HR 0.78, 95% CI 0.51-1.19, P = 0.25) and PFS of programmed death-ligand 1<1% subgroup (HR 0.85; 95%CI 0.70 to 1.03, P=0.09) in ICIs+chemotherapy over chemotherapy. Meanwhile, OS of programmed death-ligand =1-49% subgroup (HR 0.92; 95%CI 0.77 to 1.10, P=0.36) and PFS of programmed death-ligand 1≥50% subgroup (HR 0.76; 95%CI 0.52 to 1.11, P=0.15) showed no significant differences in ICIs over chemotherapy. Furthermore, fewer adverse events were observed in the ICIs groups than control groups. Conclusion: ICIs are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for ICIs.

Importance: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade. Objective: To compare the effect of ipilimumab plus sargramostim vs ipilimumab alone on overall survival (OS) in patients with metastatic melanoma. Design, setting, and participants: The Eastern Cooperative Oncology Group (ECOG) conducted a US-based phase 2 randomized clinical trial from December 28, 2010, until July 28, 2011, of patients (N = 245) with unresectable stage III or IV melanoma, at least 1 prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1. Interventions: Patients were randomized to receive ipilimumab, 10 mg/kg, intravenously on day 1 plus sargramostim, 250 μg subcutaneously, on days 1 to 14 of a 21-day cycle (n = 123) vs ipilimumab alone (n = 122). Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle. Main outcomes and measures: Primary end point: comparison of length of OS. Secondary end point: progression-free survival (PFS), response rate, safety, and tolerability. Results: Median follow-up was 13.3 months (range, 0.03-19.9). Median OS as of December 2012 for ipilimumab plus sargramostim was 17.5 months (95% CI, 14.9-not reached) vs 12.7 months (95% CI, 10.0-not reached) for ipilimumab. The 1-year survival rate for ipilimumab plus sargramostim was 68.9% (95% CI, 60.6%-85.5%) compared to 52.9% (95% CI, 43.6%-62.2%) for ipilimumab alone (stratified log-rank 1-sided P = .01; mortality hazard ratio 0.64 [1-sided 90% repeated CI, not applicable-0.90]). A planned interim analysis was conducted at 69.8% of expected events (104 observed with 149 expected deaths). Planned interim analysis using the O'Brien-Fleming boundary was crossed for improvement in OS. There was no difference in PFS. Median PFS for ipilimumab plus sargramostim was 3.1 months (95% CI, 2.9-4.6) vs 3.1 months (95% CI, 2.9-4.0) for ipilimumab alone. Grade 3 to 5 adverse events occurred in 44.9% (95% CI; 35.8%-54.4%) of patients in the ipilimumab plus sargramostim group vs 58.3% (95% CI, 49.0%-67.2%) of patients in the ipilimumab-alone group (2-sided P = .04). Conclusion and relevance: Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer OS and lower toxicity, but no difference in PFS. These findings require confirmation in larger studies with longer follow-up. Trial registration: clinicaltrials.gov Identifier: NCT01134614.

Background: Anti-PD-1 monoclonal antibodies, nivolumab and pembrolizumab, and anti-CTLA-4 antibody ipilimumab are being in clinic trials to treat melanoma. Here, we performed a meta-analysis to evaluate the efficacy and toxicity of them against advanced melanoma. Methods: Eleven reports from 6 randomized control trials on treating metastatic melanoma, which were divided into 3 subgroups, nivolumab/pembrolizumab versus chemotherapy, nivolumab versus ipilimumab, and nivolumab-plus-ipilimumab versus ipilimumab, were included and the meta-analysis was performed for each subgroup. The outcome measures were objective response rates (ORR), median progression free survival (PFS), 1-year overall survival rates (OS), and toxicity estimated by grade 3 to 4 adverse events. Results: For nivolumab/pembrolizumab versus chemotherapy, nivolumab versus ipilimumab, and nivolumab-plus-ipilimumab versus ipilimumab, the pooled risk ratios (RR) of the ORR were 3.43 (95% CI: 2.57-4.58), 2.51 (95% CI: 2.03-3.09), and 3.28 (95% CI: 2.58-4.17), respectively. The pooled HR of PFS were 0.42 (95% CI: 0.36-0.49), 0.58 (95% CI: 0.50-0.66), and 0.41 (95% CI: 0.30-0.52), respectively. The pooled RR of 1-year OS was 1.37 (95% CI: 1.08-1.74) and 1.54 (95% CI: 0.90-2.63) for nivolumab versus ipilimumab and nivolumab-plus-ipilimumab versus ipilimumab. These results suggested that anti-PD-1 monotherapy and nivolumab-plus-ipilimumab therapy had ORR and PFS benefit compared with the control group. Anti-PD-1 treatment increased 1-year OS for patients compared with ipililumab treatment. But there is no significantly difference on 1-year OS between the nivolumab-plus-ipilimumab treatment and the ipilimumab treatment group. The toxicity analysis showed that there is less risk of adverse events in the anti-PD-1 treatment group compared with the chemotherapy and ipilimumab group. Combining nivolumab with ipilimumab increased the risk for high-grade adverse events compared with ipilimumab alone but the adverse events were generally manageable. Conclusions: Anti-PD-1 monotherapy and nivolumab-plus-ipilimumab therapy improved ORR and prolonged PFS of patients with advanced melanoma and the adverse events are generally manageable. The therapy is indeed a promising approach for treatment of advanced melanoma.